EP0063109B1 - Therapeutisch wirksame Verbindungen und deren pharmazeutische Zusammensetzungen - Google Patents

Therapeutisch wirksame Verbindungen und deren pharmazeutische Zusammensetzungen Download PDF

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Publication number
EP0063109B1
EP0063109B1 EP82850072A EP82850072A EP0063109B1 EP 0063109 B1 EP0063109 B1 EP 0063109B1 EP 82850072 A EP82850072 A EP 82850072A EP 82850072 A EP82850072 A EP 82850072A EP 0063109 B1 EP0063109 B1 EP 0063109B1
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Prior art keywords
groups
group
therapeutically active
compound
bound
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EP82850072A
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English (en)
French (fr)
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EP0063109A2 (de
EP0063109A3 (en
Inventor
Rolf Erik Axel Verner Axen
Jan Per Erik Carlsson
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Pfizer Health AB
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Pharmacia AB
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0089—Oxidoreductases (1.) acting on superoxide as acceptor (1.15)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/62—Insulins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0065—Oxidoreductases (1.) acting on hydrogen peroxide as acceptor (1.11)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/96—Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)

Claims (8)

1. Verfahren zur Verlängerung der Aktivität von Verbindungen auf organischer Grundlage und mit einer Polypeptidstruktur, die eine bekannte therapeutische Aktivität besitzen, wobei die bekannten Verbindungen
(a) ein oder mehrere Carboxylgruppen und/oder
(b) ein oder mehrere primäre und/oder sekundäre Aminogruppen und/oder
(c) ein oder mehrere SH-Gruppen und/oder innere S-S- Brücken
enthalten, dadurch gekennzeichnet, daß man Gruppen (a) oder (b) durch eine Gruppe, die die Struktur -S'-S"-R umfaßt, substituiert, oder daß man Gruppen (c) in die Struktur -S'-S"-R durch an sich bekannte Methoden umwandelt, wobei
i) S"-R dadurch definiert ist, daß R eine organische Gruppe ist, die in einer physiologisch annehmbaren Verbindung H-S"-R enthalten ist, welche durch Spalten der Disulfidbrücke -S'-S" in der gekannten Struktur erhältlich ist, in welcher Verbindung H-S"-R das Schwefelatom S" an ein Kohlenstoffatom in einem heterocyclischen aromatischen Ring im R gebunden ist, der eine derartige Konfiguration hat, daß die Verbindung H-S"-R unter Aufrechterhaltung ihrer physiologischen Annehmbarkeit durch Tautomerie oder Resonanz unter Beteiligung des an R gebundenen Schwefelatoms S" stabilisiert wird, so daß sie von einer weiteren Reaktion, bei der ein Thioldisulfidaustausch stattfindet im hauptsächlichen ausgeschlossen ist, und
ii) S' an ein aliphatisches Kohlenstoffatom gebunden ist,

wobei eine solche Substitution oder Umwandlung keine ausgeprägten negativen Effekte auf die therapeutische Aktivität hat.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß ein oder mehrere der primären und sekundären Aminogruppen des Polypeptids durch eine Gruppe der Formel
Figure imgb0012
substituiert sind, wobei R, S" und S' die gleichen Bedeutungen wie oben haben, A für eine geradkettige verzweigte oder cyclische Kohlenwasserstoffkette mit 1 bis 10 Kohlenstoffatomen steht, die gegebenenfalls durch 1 bis 3 Hydroxylgruppen substituiert ist, und gegebenenfalls durch 1 bis 3 Sauerstoff- oder Schwefelatome unterbrochen ist, wobei vorzugsweise höchstens ein anderes Atom als Kohlenstoff und Wasserstoff an ein und das gleiche Kohlenstoffatom in A gebunden ist, und X 1) für die Funktion -CO-, die an das Stickstoffatom in der Aminogruppe gebunden ist, oder 2) eine direkte Bindung an das Stickstoffatom in der Aminogruppe des Polypeptids steht.
3. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß ein oder mehrere Carboxylgruppen -CO-OH des Polypeptids in ein oder mehrere Gruppen der Formel -CO-X1-A-S'-S"-R umgewandelt sind, wobei A, R, S" und S' die oben angegebenen Bedeutungen haben, und X1 für―O― oder -N(R,)- steht, wobei R1 für Wasserstoff oder eine niedere Alkylgruppe mit 1 bis 5 Kohlenstoffatomen steht.
4. Verfahren nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß das therapeutisch aktive Polypeptid ein therapeutisch aktives Protein, vorzugsweise ein therapeutisch aktives Enzym oder Hormon, ist.
5. Verfahren nach Anspruch 4, dadurch gekennzeichnet, daß das Enzym Superoxid-Dismutase oder Katalase ist.
6. Verfahren nach Anspruch 4, dadurch gekennzeichnet, daß das Hormon Insulin ist.
7. Verfahren nach einem der Ansprüche 1 bis 6, dadurch gekennzeichnet, daß R in der Struktur -S'-S"-R für 2-Benzothiazolyl, 2-Pyridyl, 5-Nitro-2-pyridyl, 4-Pyridyl, 5-Carboxy-2-pyridyl oder das N-Oxid irgendeiner der vier letztgenannten Gruppen steht.
8. Pharmazeutische Zusammensetzung, dadurch gekennzeichnet, daß sie als Wirkstoff eine therapeutisch aktive organische Verbindung, modifiziert nach dem Verfahren nach einem der Ansprüche 1 bis 7, enthält.
EP82850072A 1981-04-06 1982-04-05 Therapeutisch wirksame Verbindungen und deren pharmazeutische Zusammensetzungen Expired EP0063109B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8102194A SE8102194L (sv) 1981-04-06 1981-04-06 Terapeutiskt aktiv organisk forening och farmaceutisk beredning innehallande denna
SE8102194 1981-04-06

Publications (3)

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EP0063109A2 EP0063109A2 (de) 1982-10-20
EP0063109A3 EP0063109A3 (en) 1983-01-26
EP0063109B1 true EP0063109B1 (de) 1986-07-16

Family

ID=20343535

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US (1) US4711951A (de)
EP (1) EP0063109B1 (de)
JP (1) JPS58500482A (de)
DE (1) DE3271990D1 (de)
SE (1) SE8102194L (de)
WO (1) WO1982003394A1 (de)

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SE9004047L (sv) * 1990-12-19 1992-06-20 Francisco Batista Metod foer immobilisering av tiolfoereningar via aktivering av polymerer, aktiverade polymerer, och produkter erhaallna med metoden
US5516703A (en) * 1993-08-20 1996-05-14 The University Of Utah Coating of hydrophobic surfaces to render them protein resistant while permitting covalent attachment of specific ligands
US6284503B1 (en) 1993-08-20 2001-09-04 University Of Utah Research Foundation Composition and method for regulating the adhesion of cells and biomolecules to hydrophobic surfaces
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CN101037438A (zh) 2002-08-02 2007-09-19 沃泰克斯药物股份有限公司 用作gsk－3的抑制剂的吡唑组合物
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US7601718B2 (en) * 2003-02-06 2009-10-13 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of protein kinases
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CA2548172A1 (en) * 2003-12-04 2005-06-23 Vertex Pharmaceuticals Incorporated Quinoxalines useful as inhibitors of protein kinases
ATE542814T1 (de) * 2005-08-18 2012-02-15 Vertex Pharma Pyrazinkinaseinhibitoren
BRPI0619708A2 (pt) 2005-11-03 2011-10-11 Vertex Pharma composto, composição, método para inibir a atividade da proteìna aurora quinase numa amostra biológica, método para tratar distúrbio proliferativo e método para tratar cáncer
AU2007317435A1 (en) * 2006-11-02 2008-05-15 Vertex Pharmaceuticals Incorporated Aminopyridines and aminopyrimidines useful as inhibitors of protein kinases
NZ577768A (en) * 2006-12-19 2012-01-12 Vertex Pharma Aminopyrimidines useful as inhibitors of protein kinases
JP2010520887A (ja) * 2007-03-09 2010-06-17 バーテックス ファーマシューティカルズ インコーポレイテッド 蛋白キナーゼの阻害剤として有用なアミノピリジン
ES2435997T3 (es) * 2007-03-09 2013-12-26 Vertex Pharmaceuticals, Inc. Aminopirimidinas útiles como inhibidores de las proteínas cinasas
JP5393489B2 (ja) * 2007-03-09 2014-01-22 バーテックス ファーマシューティカルズ インコーポレイテッド 蛋白キナーゼの阻害剤として有用なアミノピリミジン
JP2010523700A (ja) 2007-04-13 2010-07-15 バーテックス ファーマシューティカルズ インコーポレイテッド キナーゼインヒビターとして有用なアミノピリミジン
MX2009011811A (es) * 2007-05-02 2010-01-14 Vertex Pharma Aminopirimidinas utiles como inhibidores de cinasa.
WO2008137621A1 (en) * 2007-05-02 2008-11-13 Vertex Pharmaceuticals Incorporated Aminopyrimidines useful as kinase inhibitors
MX2009011810A (es) * 2007-05-02 2010-01-14 Vertex Pharma Tiazoles y pirazoles utiles como inhibidores de cinasa.
MX2009012719A (es) * 2007-05-24 2010-02-04 Vertex Pharma Tiazoles y pirazoles utiles como inhibidores de cinasa.
AR067762A1 (es) * 2007-07-31 2009-10-21 Vertex Pharma Proceso para preparar 5-fluoro-1h-pirazolo (3,4-b) piridin-3-amina y derivados de la misma
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Also Published As

Publication number Publication date
EP0063109A2 (de) 1982-10-20
DE3271990D1 (en) 1986-08-21
WO1982003394A1 (en) 1982-10-14
EP0063109A3 (en) 1983-01-26
SE8102194L (sv) 1982-10-07
JPS58500482A (ja) 1983-03-31
US4711951A (en) 1987-12-08

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